An autoimmune disease is a general term for diseases in which excessive immune responses attack an individual's own normal cells and tissues, resulting in symptoms, and examples thereof include multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, or polymyalgia rheumatica.
An allergic disease is a disease derived from excessive immune responses to specific antigens, and examples thereof include allergic dermatitis, atopic dermatitis, allergic rhinitis (pollinosis), allergic conjunctivitis, allergic gastroenteritis, bronchial asthma, childhood asthma, or food allergy.
Various mechanisms have been proposed for the onset and progress of autoimmune diseases and allergic diseases. As one of these mechanisms, it is known that Th17 cells, which is one of a subset of helper T cells, and IL-17, which is an inflammatory cytokine produced by Th17 cells, play an important role in the onset and progress of autoimmune diseases and allergic diseases (Chen et al., International Immunopharmacology, 2011, Vol. 11, p. 536-542 and Hofmann et al., Current Opinion in Allergy and Clinical Immunology, 2016, Vol. 16, p. 451-457).
IL-17 acts on various cells such as fibroblasts, epithelial cells, vascular endothelial cells, and macrophages, and is involved in the induction of inflammatory cytokines, chemokines, metalloproteases and other inflammatory mediators and the migration of neutrophils. Therefore, it is considered that potent anti-inflammatory effects are shown if the production or function of IL-17 can be suppressed, and clinical studies of anti-IL-17 antibodies with indications for various autoimmune diseases have been conducted.
Recently, it became clear that retinoid-related orphan receptor γ (hereinafter referred to as RORγ), which is a nuclear receptor, functions as a transcription factor essential for the differentiation and proliferation of Th17 cells and the expression of IL-17 (Ivanov et al., Cell, 2006, Vol. 126, p. 1121-1133), and it was shown that suppression of the expression or function of RORγ results in suppression of the differentiation and activation of Th17 cells and the production of IL-17 (Jetten, Nuclear Receptor Signaling, 2009, Vol. 7, e003).
It has been reported that the expression level of RORγ in peripheral blood mononuclear cells or skin tissue in patients with autoimmune diseases (multiple sclerosis, psoriasis, systemic lupus erythematosus and the like) or patients with allergic diseases (allergic dermatitis and the like) is higher than that of healthy individuals (Hamzaoui et al., Medical Science Monitor, 2011, Vol. 17, p. CR227-234, Ma et al., Journal of the European Academy of Dermatology and Venereology, 2014, Vol. 28, p. 1079-1086 and Zhao et al., British Journal of Dermatology, 2009, Vol. 161, p. 1301-1306). It has been reported that, in a knockout mouse of RORγ, the pathological state of a mouse experimental autoimmune encephalomyelitis model, which is an animal model of multiple sclerosis, is suppressed and that symptoms of autoimmune diseases such as colitis, and symptoms of allergic diseases such as asthma, are suppressed (Ivanov et al., Cell, 2006, Vol. 126, p. 1121-1133, Leppkes et al., Gastroenterology, 2009, Vol. 136, p. 257-267 and Jetten et al., The Journal of Immunology, 2007, Vol. 178, p. 3208-3218).
Furthermore, it has been suggested that binding between RORγ and a coactivator is necessary for RORγ to function as a transcription factor (Li et al., Molecular Endocrinology, 2010, Vol. 24. p. 923-929). Therefore, an RORγ antagonist, which is a compound that inhibits the binding between RORγ and a coactivator, is expected to be useful as a therapeutic agent or preventive agent for autoimmune diseases or allergic diseases.
On the other hand, as the RORγ antagonist, N-(5-(N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)sulfamoyl)-4-methylthiazol-2-yl)acetamide (Burris et al., Nature, 2011, Vol. 472, p. 491-494), substituted azole derivatives (JP 2012-236822 A) such as 6-(2-chloro-4-methylphenyl)-3-(4-cyclopropyl-5-(3-neopentylcyclobutyl)isoxazol-3-yl)-5-oxohexanoic acid, and sulfonylbenzene derivatives (WO 2012/027965) such as N-(5-(2-chlorobenzoyl)-4-(3-chlorophenyl)thiazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide have been reported previously, but compounds having a cyclic amine structure such as 1-substituted piperidine-2-carboxamide, have not been disclosed.
As the compound having a cyclic amine structure such as 1-substituted piperidine-2-carboxamide, (S)-1-(2-(3,3-difluoropyrrolidin-1-yl)acetyl)-N-(1-ethyl-5-phenyl-1H-1,2,4-triazol-3-yl)piperidine-2-carboxamide and the like has been reported as a cannabinoid 2 receptor agonist (WO 2010/096371), and (R)-N-(5-benzyl-4-phenylthiazol-2-yl)-1-(2-cyclopentylacetyl)piperidine-2-carboxamide and the like has been reported as an acyl-coenzyme A: diacylglycerol acyltransferase 1 inhibitor (WO 2010/007046), but the effects of these compounds on RORγ have been neither disclosed nor suggested.
As the therapeutic agent or preventive agent for multiple sclerosis, (S)-(3-(5-(4-fluorobenzyl)-1,2,4-oxadiazol-3-yl)piperidin-1-yl)(4-fluorophenyl)methanone and the like has been reported as a positive allosteric modulator of a metabotropic glutamate receptor (WO 2006/129199), but concrete data on the drug efficacy of these compounds on multiple sclerosis have not been shown at all, and the usefulness has not been shown at all. In WO 2006/129199, the effects of these compounds on RORγ have been neither disclosed nor suggested, and compounds having a 1-substituted piperidine-2-carboxamide structure have not been disclosed.
For the actual treatment of autoimmune diseases and allergic diseases, steroids or immunosuppressive agents acting on the whole immune system are used as internal medicines. However, due to concerns about serious side effects such as infection, currently there are many clinical cases in which administration must be discontinued before sufficient drug efficacy is obtained. Therefore, there is a need to develop a new medicament targeted to a molecule playing an important role in the mechanism of the onset and progress of autoimmune diseases and allergic diseases.
Therefore, it could be helpful to provide a novel compound having RORγ antagonist activity and a therapeutic agent or preventive agent for an autoimmune disease or allergic disease based on the effect to suppress the function of RORγ by RORγ antagonist activity.